Abstract

Background Neurological soft signs (NSS) are minor neurological
signs indicating non-specific cerebral dysfunction. Their presence has been
documented extensively in schizophrenia but not during the first psychotic
episode.

Aims To review studies that have specifically investigated NSS at
the time of the first psychotic episode.

Method A review of studies investigating neurological function in
first-episode psychosis, using a clinical examination.

Results Patients with first-episode psychosis show an excess of NSS,
particularly in the areas of motor coordination and sequencing, sensory
integration and in developmental reflexes. Furthermore, NSS may be associated
with a specific laterality pattern.

Conclusions More studies on first-onset schizophrenia are needed,
evaluating both sensory and motor neurological domains (scoring separately for
the two sides of the body), integrating this knowledge with neuroimaging
findings and clarifying the role of NSS as markers of cognitive
dysfunction.

Neurological soft signs (NSS) are minor (‘soft’) neurological
abnormalities in sensory and motor performance identified by clinical
examination. They have been described in excess in patients with schizophrenia
(Buchanan & Heinrichs,
1989). There is still a lack of consensus on the
neurodysfunctional area underlying NSS; some authors suggest that NSS reflect
a failure in the integration within or between sensory and motor systems
(Griffiths et al,
1998), whereas others advocate deficits in neuronal circuits
involving subcortical structures (e.g. basal ganglia, brain-stem and limbic
system; Heinrichs & Buchanan,
1988). Although the presence of NSS has been documented
extensively in schizophrenia as a whole, the same cannot be said for patients
undergoing their first psychotic episode. This review will briefly describe
the NSS that have been commonly reported in patients with schizophrenia, and
then concentrate on studies that have specifically investigated NSS at the
time of the first psychotic episode.

NEUROLOGICAL SIGNS REPORTED IN SCHIZOPHRENIA

The majority of investigations into patients with schizophrenia at various
stages of chronicity have described an excess of neurological
‘
soft’ abnormalities. The term ‘soft’ was originally
used, as opposed to ‘hard’, to reflect the absence of any obvious
localised pathological lesion underlying these signs
(Tucker et al, 1974;
Quitkin et al, 1976).
This term has been employed, more recently, to indicate signs that do not
reflect primary tract or nuclear pathology
(Woods et al, 1986).
Although the categorisation of neurological signs as ‘soft’ (e.g.
frontal release and cerebellar signs) and the batteries used to measure them
have varied, neurological abnormalities in schizophrenia seem to be localised
to three main neurological domains: integrative sensory function; motor
coordination; and motor sequencing (Table
1) (Buchanan & Heinrichs,
1989). Deficits in integrative sensory function (possibly
resulting from a parietal dysfunction) are reflected in higher rates of
bilateral extinction, impaired audio—visual integration, agraphaesthesia
and astereognosis (Buchanan &
Heinrichs, 1989; Griffiths
et al, 1998). Deficits in motor coordination have been
reported through tests of general co-ordination, intention tremor,
finger—thumb opposition, balance and gait. Finally, poor performance in
complex motor tasks (possibly resulting from a dysfunction of the
frontal—basal ganglial circuitry) has been reported in tests that
involve repetitive alternating hand positions, such as the
fist—edge—palm, the fist-ring and the Ozeretski tests.

Functional areas frequently reported as abnormal in schizophrenia, and
some of the tests that can elicit disturbances in these areas

Abnormalities have also been reported in eye movements (pursuit and
saccadic movements; Stevens,
1982) and developmental reflexes
(Boks et al, 2000),
particularly in signs of frontal release. Other abnormalities, such as those
of primary sensory function, have been less often described.

NEUROLOGICAL SOFT SIGNS IN FIRST-EPISODE PSYCHOSIS

Investigating patients at the early stages of the illness has the following
potential advantages: it can clarify whether NSS are part of a
neurodysfunction that underlies schizophrenia rather than the consequence of
degenerative processes; and it can elucidate whether or not they are simply a
neuroleptic-induced epiphenomenon (i.e. a consequence of long-term
pharmacological treatment).

In considering patients with first-onset psychosis, it is important to note
that some studies have included not just patients with schizophrenia but also
those with other forms of psychosis. This over-inclusiveness is unavoidable as
assessments are frequently performed at the very early stages of a psychotic
presentation, when a diagnosis of definite schizophrenia may still be
doubtful. Not including cases until they definitely qualify for a diagnosis of
schizophrenia at a later stage would mean losing potential cases of
schizophrenia from the initial sample. Therefore, for the purpose of this
review, we will also include studies that have evaluated first-episode
psychosis as a whole.

We decided to evaluate those studies that investigated neurological
function in patients with first-episode psychosis using a clinical examination
that specifically reported on the neurological function of this group of
patients. We performed a Medline literature search of the period between 1966
and 2001 using the following terms: PSYCHIATRY and NEURO*;
SCHIZOPHRENIA and NEURO*; FIRST EPISODE and
NEURO*; FIRST EPISODE and SOFT-SIGNS; SOFT-SIGNS and NSS.
We also examined cross-references from the articles identified.

First-episode studies of NSS can be divided into: (a) studies that have
evaluated the prevalence of NSS among patients with first-episode psychosis
only (i.e. without including a comparison group); (b) studies that have
evaluated NSS in first-episode patients and compared them with healthy
controls; (c) studies that have compared first-episode patients with subjects
at high risk of developing psychosis; and finally, (d) studies that have
evaluated NSS at first-episode and then at follow-up. Unfortunately, a variety
of instruments have been used to evaluate neurological function, and not all
studies have used a published, validated instrument, often reporting on
findings derived from a ‘clinical neurological assessment’, which
makes comparison of the results difficult
(Table 2).

The prevalence of NSS among first-episode psychosis patients

Studies that evaluated patients with first-episode psychosis have reported
a high prevalence of NSS, the percentage of patients with NSS varying from 20%
(The Scottish Schizophrenia Research
Group, 1987) to 97.1% (Browne
et al, 2000). The Scottish Schizophrenia Research Group
(1987) used the Northwick Park
Brief Neurological Assessment (Cunningham
Owens & Johnstone, 1980); abnormalities were observed
particularly in plantar responses and coordination (as well as weakness in
lower limbs), diminished tone in lower limbs and increased ankle and knee
jerks.

The study by Browne et al
(2000) is noteworthy in that
information was collected using two validated scales: the Neurological
Evaluation Scale (NES; Buchanan &
Heinrichs, 1989) and the Condensed Neurological Examination (CNE;
Rossi et al, 1990).
The results of the two scales were correlated strongly; at least one NSS
(defined as one NES item rated 2) was displayed by 97.1% of patients, with 63%
showing at least two NSS (defined as 2 or more NES items rated 2).

The prevalence of NSS in patients with first-episode psychosis in
comparison with healthy controls

The prevalence of NSS in healthy subjects has been reported to vary from 5%
(Hertzig & Birch, 1968;
Rochford et al, 1970)
to more than 50% (Kennard,
1960; Cox & Ludwig,
1979), the proportion reported being mainly a function of the
measure used. It is therefore advantageous to compare the rates of NSS in
patients with first-episode psychosis with those of healthy controls, using
identical assessment procedures.

In the study by Flyckt et al
(1999), patients with
first-episode schizophrenia and patients with chronic schizophrenia were
compared as a whole with healthy controls. The patient group reported
significantly higher NSS scores than the controls, and although the absolute
figures were not reported separately for chronic and first-episode patients,
the authors commented that there were no differences between first-episode and
chronic patients.

We can conclude that the rates of neurological signs in patients at their
first-episode of psychosis are already higher than those of healthy controls.
Furthermore, these rates are comparable with those described in studies of
schizophrenia as a whole, which have reported an excess of NSS, particularly
for motor coordination, in 59-92% of patients
(Tucker et al, 1975).
A higher consistency in rates could be achieved if the assessors were blind to
the subject's status, a task easier to achieve if patients with other
psychiatric disorders represent the control group. Considering that NSS rates
similar to those observed in schizophrenia have been reported in patients with
personality disorder (Rochford et
al, 1970), it seems important that subjects with
schizophrenia are also compared with subjects affected by other putative
neurodevelopmental disorders (e.g. obsessive—compulsive disorder,
attention-deficit hyperactivity disorder).

The prevalence of NSS in patients with first-episode psychosis in
comparison with high-risk subjects

Having established that an excess of NSS is already present in the early
phases of psychosis, the next question is whether or not this excess pre-dates
the onset of psychosis and thus could be a vulnerability marker for psychosis.
Impairments of motor development and fine motor coordination have been
observed in children from cohort studies who later go on to develop
schizophrenia (Crow et al,
1995; Cannon et al,
1999). The presence of these abnormalities suggests that
neurological dysfunction could reflect a neurodevelopmental abnormality that
puts the individuals at risk of later schizophrenia.

Much attention has been devoted to asymptomatic subjects at high genetic
risk of schizophrenia, with similar abnormalities having been reported
(Rieder & Nichols, 1979;
Fish et al, 1992;
Marcus et al, 1993).
In one study (Carr et al,
2000), subjects at first-episode psychosis were compared with
high-risk asymptomatic individuals, and were reported as showing similar NSS
rates. In another study, although first-episode patients showed more NSS than
high-risk subjects, high-risk subjects had an excess of NSS compared with
healthy controls, specifically for signs of sensory integration
(Lawrie et al,
2001).

These findings suggest that neurological dysfunction observed in
first-episode patients is at least in part related to the pathogenesis
underlying the illness, and can be observed in association with an increased
risk of the disorder, even before the onset of a full-blown psychotic illness
(Lawrie et al, 2001).
This is consonant with reports of neurological abnormalities not only in the
relatives of patients with schizophrenia
(Kinney et al, 1986;
Griffiths et al,
1998; Niethammer et
al, 2000), but also in the offspring of parents with
schizophrenia (Fish & Hagin,
1973; Marcus et al,
1985). In these latter cases, the neurological abnormalities were
similar to those described in adult patients: problems in coordination, motor
dysfunction and sensory integration
(Heinrichs & Buchanan,
1988).

The temporal stability of NSS following the first psychotic
episode

If we accept the above evidence that NSS are already present at first onset
and indeed in vulnerable asymptomatic high-risk individuals, the question of
their temporal stability can only be addressed by follow-up studies.

The only study that we have identified that investigated NSS at both first
onset and at follow-up is that of Madsen et al
(1999). At the time of their
first psychotic episode, patients showed a significantly higher total rate of
neurological abnormalities than healthy controls. Five years later, the
difference between patients with schizophrenia and healthy controls was
increased, especially for frontal, corticospinal and temporo-parietal
functions. By contrast, patients with other psychiatric disorders showed a
reduction in the number of neurological abnormalities at follow-up, indicating
that their neurological function improved with remission, although they still
showed significantly higher rates of neurological abnormalities than healthy
controls, mainly in frontal lobe functions. Thus, this study suggests a
progression of neurological dysfunction comparable to that previously reported
in chronic patients with schizophrenia
(Torrey, 1980), although
treatment effects could have contributed to this.

Thus NSS, particularly in motor coordination and in developmental reflexes,
are already present in patients at very early stages of the illness.
Furthermore, the neurological anomalies shown by patients undergoing their
first episode of schizophrenia do not improve with time and may actually
deteriorate. A similar neurological dysfunction is present even in high-risk
subjects without psychosis. This is in accord with previous evidence that an
impairment of motor development and fine motor coordination can predict
schizophrenia-spectrum disorders in adult-hood
(Crow et al, 1995),
and may be part of a genetically transmitted vulnerability to develop
schizophrenia, as suggested by studies on children at high genetic risk
(Rieder & Nichols, 1979;
Fish et al, 1992;
Marcus et al,
1993).

The majority of the first-episode studies reviewed did not evaluate the
relationship between neurological function and familiality. Three studies
(Flyckt et al, 1999;
Madsen et al, 1999;
Lawrie et al, 2001)
evaluated family history or genetic loading and neurological function and
reported no association between prevalence of NSS and family history. However,
a relationship was reported between family history and a specific laterality
pattern in psychomotor performance in one study
(Flyckt et al, 1999),
and family history and progression of neurological dysfunction in another
(Madsen et al,
1999).

In the study by Madsen et al
(1999), information was
obtained on psychiatric disorders in the first- and second-degree relatives.
Although there was no association between a positive family history of
psychosis and NSS at first presentation, the patients with a history of
psychotic disorder in first-degree relatives showed a significant neurological
deterioration at follow-up.

The report of no association between positive family history and
neurological dysfunction in these first-episode studies is in contrast with
previous observation of a relationship between the two reported in patients at
various illness stages. However, it is possible that, if a positive family
history is associated with more progression in neurological dysfunction,
studies of patients in more advanced stages of schizophrenia could have had
more chances of identifying this association, less evident in the initial
stages of the illness. It is, however, difficult to draw a conclusion from the
few studies reported.

LATERALITY AND CEREBRAL DOMINANCE

To date, research has not identified an unequivocal laterality pattern of
neurological signs in schizophrenia in general (and by implication a lesion of
a particular hemisphere). Some studies have reported a predominance of
neurological abnormalities on the right side of the body
(Torrey, 1980;
Caligiuri & Lohr, 1994),
but there are conflicting reports of higher scores for NSS on the left side of
the body (Niethammer et al,
2000).

The first-onset study of Browne et al
(2000) evaluated the
relationship of mixed-handedness (measured with the Edinburgh Inventory;
Oldfield, 1971) to NSS. In the
Edinburgh Inventory, subjects are asked to perform 10 common activities and a
laterality quotient is then calculated. The authors reported that narrowly
defined mixed-handed subjects (two or more discrepancies in hand preference)
performed worse on both the NES and the CNE examinations, in comparison with
lateralised individuals. Although the number of mixed-handed subjects was
small, this raises the possibility that individuals whose handedness is not
lateralised have poorer motor coordination than those with a lateralised hand
preference. This finding should be interpreted along with the reported excess
of mixed-handedness in patients with psychosis, and especially with
schizophrenia (Cannon et al,
1995; Malesu et al,
1996; Orr et al,
1999).

Mixed-handedness in schizophrenia has been postulated by Crow
(1997) to reflect an
abnormality of cerebral dominance. Possible relevant information comes from
our preliminary report (Dazzan et
al, 2001) of a worse neurological performance (especially for
coordination and sequencing) on the left side of the body in a group of 145
subjects with first-episode psychosis. A common neurodevelopmental fault can
underlie both the excess of mixed-handedness in schizophrenia and that of an
abnormal neurological function (possibly lateralised to one side of the body),
which was particularly marked in these subjects.

The study by Flyckt et al
(1999) evaluated both patients
with schizophrenia (some at first-episode and some in more advanced stages)
and their parents. There were no differences in NSS between patients positive
or negative for family history. However, probands and relatives were also
asked to perform the finger-tapping test, a test of psychomotor performance. A
significant difference was observed in the laterality pattern of patients and
parents who were family-history positive, compared with patients and parents
who were family-history negative. More specifically, in this test, patients
and parents who were family-history positive improved their performance with
the preferred hand, whereas the family-history negative parents neither
significantly improved nor decreased their performance with the preferred hand
over time. Considering that the finger-tapping test can provide information on
cerebral laterality (Gorynia &
Uebelhack, 1992), and that an abnormal pattern of hemispheric
asymmetry has been reported in families multiply affected by schizophrenia
(Sharma et al, 1999),
it is possible that the association between family history and a specific
laterality pattern could reflect an inherited predisposition to this
illness.

ROLE OF ANTIPSYCHOTIC MEDICATION IN NEUROLOGICAL PERFORMANCE

Could side-effects of antipsychotic medication in general, and tardive
dyskinesia in particular, explain the excess of NSS in subjects with
psychosis? No association between past and current neuroleptic exposure and
presence of NSS has been found (Ismail
et al, 1998). Indeed, most studies have failed to find
any association between tardive dyskinesia and NSS
(Wegner et al, 1985;
King et al, 1991;
Mohr et al, 1996). In
an attempt to control for the possible contribution of neuroleptic medication
to NSS, scales for extrapyramidal symptoms, akathisia and tardive dyskinesia
have been used in studies of NSS; results have shown that these neurological
abnormalities cannot be simply considered a medication effect
(Griffiths et al,
1998).

However, more definitive information on the effect of antipsychotics on
neurological function can be obtained by studying neuroleptic-naïve
subjects who have never been exposed to pharmacological treatment, or subjects
at their first psychotic episode, who have not been exposed to long-term
pharmacological treatment.

Studies on neuroleptic-naïve first-episode patients consistently
report higher NSS rates in these subjects than in healthy controls. Madsen
et al (1999) compared
neuroleptic-naïve subjects with first-episode schizophrenia or
schizophreniform disorder with healthy control subjects;
neuroleptic-naïve patients showed significantly higher rates of
neurological abnormalities than controls. Flyckt et al
(1999) examined first-episode
and chronic patients together. There were no differences in NSS between
medicated and non-medicated subjects, except for facial expression. There was
no correlation between NSS and either the daily dosage of medication or the
length of treatment.

Browne et al (2000)
reported that the rates of NSS did not differ significantly in
neuroleptic-naïve or neuroleptic-treated patients, with 97.1% of
neuroleptic-naïve subjects with psychosis showing at least one
neurological sign. This rate is much higher than the rate reported from other
studies (Gupta et al,
1995), and could have been related to differences in the
sensitivity of the assessment and the scoring guidelines used. For example, in
the study by Gupta et al
(1995) the assessment did not
include signs of frontal lobe dysfunction, which are considered the tests most
likely to identify the motor disturbance present in schizophrenia
(Manschreck et al,
1981). This is also supported by the findings of Cuesta et
al (1996), who evaluated
frontal signs through motor coordination and sequencing of complex motor tasks
and reported rates of NSS in neuroleptic-naïve patients as high as those
of Browne and colleagues.

Indirect evidence that NSS are not related to neuroleptic treatment also
comes from the study of Lawrie et al
(2001). They reported how the
excess of sensory integration signs was similar in both first-episode patients
and high-risk subjects, and significantly higher than in healthy controls,
suggesting that NSS represent a neurodevelopmental risk factor for
schizophrenia rather than being the consequence of having been exposed to
neuroleptic treatment.

Surprisingly, some authors have proposed a hypothetical protective effect
of antipsychotics on neurological dysfunction. For example, in the follow-up
study by Madsen et al
(1999), there was an increase
in NSS in patients with schizophrenia 5 years after their first present ation;
this increase was more marked in those patients who had been free of
medication for the time of the entire follow-up. Signs related to the
corticospinal tract were over-represented. The authors reported how the
neuroleptic load in non-responder patients was inversely related to change in
total neurological abnormalities. It is also possible that the positive effect
observed is related to the efficacy of antipsychotics on the clinical
presentation.

Thus, first-episode studies demonstrate that the neurological dysfunction
observed could not be interpreted as the consequence of neuroleptic
medication, and one study suggests that antipsychotics may, directly or
indirectly, improve the baseline neurological dysfunction. However, it is
important that future studies addressing this issue include in their battery
signs of frontal lobe dysfunction, because these best reflect the motor
abnormalities typical of schizophrenia, rather than those related to
neuroleptic use.

NEUROLOGICAL SOFT SIGNS AND DEMOGRAPHIC CHARACTERISTICS

Studies of patients at various stages of schizophrenia other than at
first-episode have generally failed to report any consistent association
between neurological abnormalities and socio-demographic characteristics of
patients (Ismail et al,
1998). However, there have been isolated reports of NSS being
increased especially in male patients with schizophrenia
(Heinrichs & Buchanan,
1988), or more dependent on age and duration of illness
(Lane et al, 1996;
Blyler et al, 1997;
Malla et al, 1997).
When trying to disentangle whether these associations are part of the
underlying aetiopathological process, or simply its epiphenomena, it is
important to control for these variables.

Male patients were described as having a significant increase in the number
of neurological abnormalities 5 years after onset in a follow-up study by
Madsen et al (1999).
In this sample, males were also more likely to have been subjected to maternal
obstetric complications and a non-remitting course of the illness. In the
Scottish Schizophrenia Research Group's study
(1987), most of the
non-responders were males with neurological impairment. It is possible that
the excess of neurological abnormalities in male patients, together with an
increased risk of neuro-developmental damage and of a generally more severe
illness (Castle & Murray,
1991; Bullmore et al,
1995), is part of a greater vulnerability of the developing male
brain to environmental insults (Murray,
1994).

The presence of a neurodevelopmental abnormality may also explain the
reported association between lower educational achievement and higher rates of
NSS in first-episode studies (Rubin et
al, 1994). However, the evidence derived from the study by
Browne et al (2000) is
indirect. In fact, in their study a significant difference in years of
education was present between mixed-handed and lateralised patients, with the
mixed-handed patients having a significantly lower number of years of
completed education. As mixed-handed patients showed more neurological
abnormalities, the authors speculated that neurological abnormalities were
also associated with lower years of education. These results should be
interpreted cautiously; it is likely that patients with more severe forms of
the disease, and with higher rates of neurological abnormalities, would have
found it more difficult to continue their education.

Nevertheless, the above results are consonant with evidence of an
association between IQ and neurological abnormalities, specifically between IQ
and signs of sensory integration (Kennard,
1960; Mosher et al,
1971; Arango et al,
1999). It has been suggested that the concomitant presence of NSS
and cognitive deficits in schizophrenia could reflect a diffuse, generalised
brain disorder (Kolakowska et al,
1985; King et al,
1991; Flashman et al,
1996). The line between some NSS and selected neuropsychological
tests is often difficult to draw: evaluating these together could provide
comprehensive information on a range of regional neurological dysfunctions.
Even just IQ, which has been extensively evaluated in previous studies, has
not been frequently examined in first-episode studies on NSS.

NEUROLOGICAL SOFT SIGNS AND BRAIN STRUCTURAL ABNORMALITIES

Clarifying the relationship between brain structure and neurological
dysfunction could point to the anatomical substrates of NSS present in
schizophrenia. Unfortunately, only a few studies of chronic patients have
examined this relationship. The presence of NSS has been associated with an
enlargement of cerebral ventricles
(Weinberger & Wyatt,
1982), and with smaller brain areas
(DeMyer et al, 1988),
whereas no correlation has been found between NSS and the calculated ratio
between the width of the ventricles and the brain
(Kolakowska et al,
1985).

Among first-episode studies, the only one that evaluated this relationship
was the computerised tomography (CT) study by Rubin et al
(1994). This study reported an
association between NSS and shorter brain length and wider left Sylvian
fissure, together with a tendency for patients with more neurological
abnormalities to have smaller brain volume, more cerebrospinal fluid in the
sulci and cisterna on the brain surface, increased width of the right Sylvian
fissure and smaller temporal horn volume. As in previous studies
(Kolakowska et al,
1985), there was no indication that NSS were associated with
greater volume of lateral ventricles. The findings of this study suggest that
neurological abnormalities could be associated with cortical rather than
subcortical lesions. More studies with large samples, investigating the
anatomical correlates of neurological signs specifically selected to explore
regional function/dysfunction, are needed before firm conclusions can be
drawn.

RELATIONSHIP BETWEEN NSS AND THE PSYCHOPATHOLOGY AND COURSE OF
SCHIZOPHRENIA

Similar conflicting results have also characterised studies that evaluated
the relationship between psychopathology and NSS in first-episode psychosis.
For example, Browne et al
(2000) described an association
between NSS and total symptom severity and positive symptoms whereas others
have reported no association with global measures of psychopathology
(Sanders et al,
1994), or with positive and negative dimensions of schizophrenia
(Flyckt et al, 1999).
A possible reason for the inconsistency of these results lies in the different
scale used to measure NSS. For example, Flyckt et al
(1999) did not use a scale
that included factors involving attention and initiative. As Browne et
al (2000) suggested, the
correlation between total NSS and positive symptoms may reflect attentional
deficits secondary to untreated symptoms. Not only is the number of
first-episode studies small, but some studies also lacked sufficient power to
evaluate such associations.

The majority of first-episode studies report no correlation between NSS and
age at onset (Madsen et al,
1999), duration of untreated psychosis (Madson et al,
1999; Browne et al,
2000), global assessment of functioning
(Sanders et al,
1994), and occupational outcome
(Johnstone et al,
1990). It is possible that factors such as occupational outcome
and global assessment of functioning are worse in more advanced phases of the
illness, and are therefore not associated with neurological dysfunction in the
initial stages. However, two studies described an association between NSS and
both poorer premorbid social adjustment
(Browne et al, 2000)
and number of in-patient days (Johnstone
et al, 1990). These associations could be related to the
fact that higher rates of signs are part of a more severe clinical picture,
which could for example explain the longer time spent in hospital; it is also
possible that this is reflected in longer pharmacological treatment, which
could in turn give rise to more NSS.

In conclusion, the studies reviewed confirm that an excess of NSS is
already evident in patients suffering their first-episode of schizophrenia or
psychosis, and indeed in high-risk subjects without psychosis. Neurological
performance appears to be worse in the areas of motor coordination and
sequencing, in sensory integration and in developmental reflexes. These minor
neurological anomalies are found particularly in males and in subjects with
lower education, and possibly in those with a more severe clinical picture.
The presence of neurological abnormalities cannot be explained away as a
consequence of neuroleptic use, although higher NSS scores are observed in
those first-episode subjects on neuroleptic treatment. For an optimal
differentiation of the motor disturbance typical of schizophrenia from the
side-effects of neuroleptic treatment, it is important that signs of frontal
lobe dysfunction are included in the assessment.

First-episode studies also support an association between neurological
signs and a specific pattern of laternality, as suggested by their particular
excess in mixed-handed subjects, and by some preliminary reports of their
lateralisation to one side of the body. This abnormal laterality pattern in
psychomotor performance is more frequently accompanied by a positive family
history of psychosis, and is present in relatives without psychosis that are
positive for family history. It is possible that this could be related to the
evidence that, as part of the genetic vulnerability to develop schizophrenia,
the cerebral hemispheres develop less asymmetrically. These findings support
the notion that neurological signs mainly result from a genetic vulnerability
rather than neurodegeneration, or the consequences of the illness
(pharmacological treatment, institutionalisation). Future studies should
therefore attempt to identify whether any NSS is specific and discriminative
of schizophrenia, as opposed to other psychiatric disorders.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

A neurological dysfunction is already evident in patients having their
first-episode of schizophrenia or psychosis, and is not the result of illness
progression.

The presence of neurological abnormalities in schizophrenia cannot be
explained away as a consequence of neuroleptic use.

The presence of a neurological dysfunction in schizophrenia may
contribute to identifying subjects at risk of a poor prognosis, who may
benefit from early intervention.

LIMITATIONS

The number of studies investigating neurological performance in
first-episode psychosis is still small.

A variety of instruments have been used to evaluate neurological
function, and this makes comparison of the results difficult.

The majority of first-episode psychosis studies did not investigate
neurological performance separately for the two sides of the body, hampering
the understanding of the role of lateralisation in neurological
dysfunction.

Acknowledgments

We thank Drs Ken G. Orr and Brian T. Toone for their useful comments on the
manuscript. We are also grateful to the Stanley Foundation and Medical
Research Council (UK) for financial support.

Footnotes

↵* Presented in part at the European First Episode Schizophrenia Network
Meeting, Whistler BC, Canada, 27 April 2001.